Mycolactone

Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic mycobacteria species including M. ulcerans, M. liflandii (an unofficial designation), M. pseudoshottsii, and some strains of M. marinum. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM.^[1][2]

Mycolactone

Names
Preferred IUPAC name (6S,7S,9E,12R)-12-[(2S,4E,6R,7R,9R)-7,9-Dihydroxy-4,6-dimethyldec-4-en-2-yl]-7,9-dimethyl-2-oxo-1-oxacyclododec-9-en-6-yl (2E,4E,6E,8E,10E,12S,13S,15S)-12,13,15-trihydroxy-4,6,10-trimethylhexadeca-2,4,6,8,10-pentaenoate
Identifiers
CAS Number	222050-77-3 Y
3D model (JSmol)	Interactive image
ChemSpider	4445303 Y
MeSH	Mycolactone
PubChem CID	5282079
CompTox Dashboard (EPA)	DTXSID10415207
InChI InChI=1S/C44H70O9/c1-28(13-11-14-29(2)25-39(48)40(49)27-37(10)46)21-30(3)18-20-44(51)52-41-15-12-16-43(50)53-42(19-17-31(4)22-34(41)7)35(8)24-32(5)23-33(6)38(47)26-36(9)45/h11,13-14,17-18,20-21,23,25,33-42,45-49H,12,15-16,19,22,24,26-27H2,1-10H3/b14-11+,20-18+,28-13+,29-25+,30-21+,31-17+,32-23+/t33-,34+,35+,36-,37+,38-,39+,40+,41+,42-/m1/s1 Y Key: WKTLNJXZVDLRTJ-QRRXZRELSA-N Y InChI=1/C44H70O9/c1-28(13-11-14-29(2)25-39(48)40(49)27-37(10)46)21-30(3)18-20-44(51)52-41-15-12-16-43(50)53-42(19-17-31(4)22-34(41)7)35(8)24-32(5)23-33(6)38(47)26-36(9)45/h11,13-14,17-18,20-21,23,25,33-42,45-49H,12,15-16,19,22,24,26-27H2,1-10H3/b14-11+,20-18+,28-13+,29-25+,30-21+,31-17+,32-23+/t33-,34+,35+,36-,37+,38-,39+,40+,41+,42-/m1/s1 Key: WKTLNJXZVDLRTJ-QRRXZRELBE
SMILES O=C1O[C@H](C/C=C(/C[C@@H]([C@@H](OC(=O)\C=C\C(=C\C(=C\C=C\C(=C\[C@H](O)[C@@H](O)C[C@@H](O)C)C)C)C)CCC1)C)C)[C@@H](C)CC(=C/[C@@H](C)[C@H](O)C[C@H](O)C)/C
Properties
Chemical formula	C44H70O9
Molar mass	743.021
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

In humans, mycolactone is the toxin responsible for Buruli ulcers, doing so by damaging tissues and inhibiting the immune response.^[3]

Variants

Five distinct, naturally occurring mycolactone structural variants have been described so far:

• Mycolactone A/B (M. ulcerans from Africa, Malaysia, Japan^[4]
• Mycolactone C (M. ulcerans from Australia)^[5]
• Mycolactone D (M. ulcerans from China)
• Mycolactone E (M. liflandii from Sub-Saharan Africa)^[6][7]
• Mycolactone F (M. pseudoshottsii and M. marinum from around the world)^[8][9]

Biosynthesis

Mycolactone consists of a 12-membered macrolide core with an ester-linked polyketide chain. Three plasmid-encoded polyketide synthase (PKS) enzymes are responsible for its production: MLSA 1 and MLSA 2 which generate the core, and MLSB is responsible for the synthesis of the polyketide chain. As shown in Figure 1, MLSB (1.2 MDa) contains seven consecutive extension modules and MLSA 1 (1.8 MDa) consists of eight. The remaining PKS enzyme, MLSA 2, contains the ninth module of MLSA.^[10] The C-terminal domains of both MLSA2 and MLSB includes a thioesterase (TE) that was thought to catalyze the formation of the mycolactone core but appears inactive.^[11] Each module consists of either malonyl-CoA or methylmalonyl-CoA Acyltransferase (AT) that allows for chain extension, a ketosynthase (KS), which catalyzes chain elongation, and an Acyl carrier protein (ACP) where the growing polyketide chain is attached. Modules may also consist of any of the following modifying domains: a dehydratase (DH), an enoyl reductase (ER) and one of two types of ketoreductase (KR) domains. Type A and B KRs refer to the two directions of ketoreduction that are correlated with specific amino acids in the active site. Four of the DH domains are predicted to be inactive based on a point mutation found in the active site sequence.^[10][12]

Domain organization of mycolactone.

Figure 1. Domain Organization of Mycolactone.^[10]